Regulation of apoptosis signal-regulating kinase 1 by LATS2 Open Access

Rusnak, Lauren (Spring 2018)

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Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase (MAP3K) protein which leads to phosphorylation and activation of mitogen activated protein kinases (MAPKs). ASK1 is as a pro-apoptotic signaling protein that is activated by a variety of cellular stressors. Because of its central role in promoting cell death, the activity of ASK1 is tightly regulated by protein-protein interactions and post-translational modifications. Deregulation of ASK1 activity has been linked to human diseases, such as neurological disorders, viral infections, and cancer. Here we describe the identification and characterization of large tumor suppressor 2 (LATS2) as a novel binding partner for ASK1. LATS2 is a core kinase within the Hippo signaling pathway and is commonly lost or downregulated in lung cancer. Lower LATS2 expression correlates with a worse prognosis in patients, highlighting the clinical importance of this protein to human cancer. We found that LATS2 interacts with ASK1 and increases downstream activation of c-Jun NH2-terminal kinase (JNK) MAPKs. These observed signaling changes are dependent on ASK1 kinase activity, indicating it is the upstream MAP3K protein responsible for transducing LATS2-mediated activation of JNK. Additionally, co-expression of LATS2 and ASK1 increase cell death. This work identifies LATS2 as a novel regulator of the ASK1-JNK signaling pathway.

Table of Contents

Chapter 1: Introduction, 1-38 Chapter 2: Methods, 39-46 Chapter 3: Large tumor suppressor 2 activates JNK in a kinase-independent mechanism through apoptosis signal-regulating kinase 1, 47-73 Chapter 4: Conclusions and future directions, 74-86 Chapter 5: References, 87-134

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